Vertebrates possess the ability to mount an immune response as a defense against pathogens from the environment as well as against aberrant cells, such as tumor cells, which develop internally. This can take the form of innate immunity, which is mediated by NK cells, neutrophils and cells of the monocyte/macrophage lineage, or the form of acquired or active immunity against specific antigens mediated by lymphocytes. Active immune responses can be further subdivided into two arms, the humoral response which entails the production of specific antibodies that serve to neutralize antigens exposed to the systemic circulation and aid in their uptake by professional phagocytic cells, and the cellular arm which is required for recognition of infected or aberrant cells within the body.
In both cases the specific response is regulated by the intracellular processing and recognition of the antigen by effector T-cells. Mature cytolytic T lymphocytes (CTLs) or T helper cells (Th) in general remain in a resting state unless they encounter antigens that their receptors can recognize in the context of MHC class I or II molecules. Upon encountering the specific antigens, the T-cells proliferate and perform effector functions, the result of which is elimination of the reactive antigens. When the antigen is processed through the cytoplasmic route, the resulting peptides are bound to nascent MHC class I molecules which facilitate appropriate presentation to effector T-cells. MHC class I presentation favors recognition by cytotoxic T lymphocytes (CTLs) that carry the CD8 ligand. In contrast, intracellular processing via the endocytic route results in presentation on MHC class II molecules which favors T helper responses involved in stimulation of both, humoral and cellular arms. The goal of vaccination is to prime both responses and generate memory T cells, such that the immune system is primed to react to a pathogenic infection. Engagement of both the humoral and cellular immune responses leads to broad based immunity and is the preferred goal for intracellular pathogens.
Activation of the T cells entails the generation of a series of chemical signals (primarily cytokines) that result in direct action or stimulation of other cells of the immune system to act. In the case of activation by class I MHC-antigen, CTLs proliferate and act to destroy infected cells presenting that given antigen in form of an MHC bound peptide. Killing an infected cell prevents the virus from proliferating and makes it accessible to neutralizing antibodies, and hence permitting elimination of the virus. In contrast, activation of Th cells by class II MHC-antigen complexes does not destroy the antigen presenting cell (which is part of the host's defense system) but rather stimulates the Th cell to proliferate and generate signals (again primarily cytokines) that affect various cells. Among other consequences, the signaling leads to B cell stimulation, macrophage activation, CTL differentiation and promotion of inflammation. This concerted response is relatively specific and is usually directed to foreign elements bearing the peptide presented by the class II MHC system.
When operating properly, the immune response is surprisingly effective at eliminating microscopic pathogens and, to a lesser extent, neoplastic cells. In general, the complicated mechanisms for self-recognition are efficient and allow a strong response to be directed exclusively at eliminating foreign antigens. The regulation of self/non-self discrimination, which is a critical function of the immune system, involves multiple mechanisms during the development and life-span of T and B lymphocytes. Whereas deletion of self-reactive T and B cell precursors in the central lymphoid organs eliminates most of the autoreactive cells, the peripheral mechanisms that require Fas, IL-2R and CTLA-4 mediated signaling are thought to be crucial for the immune homeostasis. Unfortunately, the immune system occasionally malfunctions and turns against the cells of the host thereby provoking an autoimmune response. Autoimmunity or autoreactivity typically occurs when antigen receptors on immune cells recognize specific self-antigens (e.g. self-epitopes) on host cells and initiate reactions that result in the destruction of the host cells. In many cases, autoimmune reactions are self-limited in that they disappear when the antigens that provoked them are cleared away. However, in some instances the autoreactive lymphocytes survive longer than they should and continue to induce apoptosis or otherwise eliminate host cells. Some evidence in animals and humans indicates that extended survival of autoreactive cells is implicated in at least two chronic autoimmune disorders, systemic lupus erythematosus and rheumatoid arthritis.
Other mechanisms of action are also thought to contribute to the development of various autoimmune disorders. For example, over the last few years it has become clear that the avidity of T cell-APC interactions dictates thymic learning and tolerance to self antigens. Accordingly, high avidity interactions lead to elimination of the T cell whereas low avidity interactions allow for maturation and exit from the thymus. Although this mechanism is effective in purging the immune system of autoreactivity, T cell precursors endowed with self reactivity could still be generated and migrate to the periphery if the autoantigen is sequestered and does not achieve effective levels of thymic presentation, is subjected to thymic crypticity or is poorly presented. Moreover, superantigens capable of reacting with particular T cell receptors and events that could stimulate antigen mimicry, epitope spreading or peripheral loosening in peptide crypticity may trigger activation of those self-reactive T cells and cause antigen exposure. In any case, continuous supply of autoantigen and abundant generation of T cell receptor ligands (peptide-MHC complexes) are a likely mechanism of T cell aggressiveness. Examples of conditions resulting from a spontaneous break in self-tolerance include multiple sclerosis (MS), rheumatoid arthritis (possibly more than one mechanism), lupus erythrematosis and type I diabetes all of which are thought to be T cell mediated autoimmune diseases (myaestenia gravis-break from self tolerance but Ab driven, inflammatory bowel disease (Chrohn's)).
One of the most likely scenarios regarding the pathogenesis of an autoimmune disease like type I diabetes, may begin with abnormal regulation of autoreactive T cells either due to bystander activation or due to molecular mimicry. For example, a viral infection or exposure to a superantigen may provide sufficient co-stimulation resulting in activation of few low affinity autoreactive T cells that escape the thymus selection. Abnormal down-regulation of such autoreactive responses may lead to expansion of pathogenic T cells that infiltrate the organ where the recognized antigen is present. A few host-related factors facilitate the transition between non-pathogenic autoreactivity and autoimmune disease: leaky central negative selection allowing the escape of higher numbers of autoreactive precursors; impaired peripheral tolerance due to abnormalities involving receptors or ligands that mediated down-regulation of lymphocyte activity; a bias to generate Th1 pro-inflammatory responses as opposed to more balanced Th1/Th2 responses; high frequency and abnormal activity of professional APCs. Local inflammation and direct destruction of host cells trigger antigen release, uptake by professional APCs and presentation to specific T cells, thus perpetuating a positive feed-back that exacerbates the autoimmunity. Simultaneously, normally cryptic, organ-associated antigens may become exposed in the context of activation of professional antigen presenting cells and antigen release, resulting in activation of T cells specific for these other self antigens. Particularly in conditions favoring overall Th1/Th2 imbalance, the employment of additional specificities may accelerate the disease. It is widely believed that whereas Th1 cytokines like IFN-γ contribute to the pathogenesis of autoimmunity, Th2 cytokines like IL-4 and IL-10 may suppress the activity of pathogenic Th1 or Tc1 cells.
Regardless of which mechanism is responsible for the malfunction of the immune system in autoimmune diseases, the results can be devastating to the individual. For example, multiple sclerosis is a chronic, inflammatory disorder that affects approximately 250,000 individuals in the United States. The inflammatory process occurs primarily within the white matter of the central nervous system and is mediated by activated T cells, B cells and macrophages which are responsible for the demyelination of the axons. Although the clinical course can be quite variable, the most common form is manifested by relapsing neurological deficits including paralysis, sensory deficits and visual problems.
In another debilitating autoimmune disease, insulin-dependent diabetes mellitus (IDDM, type I diabetes or juvenile diabetes), the immune system attacks the insulin-producing beta cells in the pancreas and destroys them. A person with IDDM produces little or no natural insulin and requires daily injections of the hormone to stay alive. Each year, from 11,000 to 12,000 children are diagnosed with IDDM and, among the more than 7 million people in the United States who are being treated for diabetes, about 5 to 10 percent have IDDM. In young people, acute complications due to inadequately controlled glucose fluctuations pose the greatest threat to survival for people with IDDM. As people grow older, long-term complications resulting from damage to organs due to blood vessel deterioration become more important, resulting in, for example, peripheral neuropathy, nephropathy, and retinal degeneration.
Treatments for autoimmune diseases have reached limited success. For example, it is often possible to correct organ-specific autoimmune disease through metabolic control. Where function is lost and cannot be restored, mechanical substitutes or tissue grafts may be appropriate. However, although it may be possible to alleviate some of the symptoms no effective long-term curative treatment exists for several of the most disabling autoimmune disorders, including multiple sclerosis and IDDM. While a number of compounds, including insulin, corticosterioids and modified beta interferon, can ameliorate some of the symptoms of autoimmune diseases, they have proven to have serious side effects and/or require long term use.
Other avenues of treatment have shown promise in preclinical animal model studies but have yet to be shown to be effective in humans. One such therapy is the suppression of pathogenic lymphocytes by treatment with specific antigens. Such treatment may have the critical advantage of addressing only the specific T cells, while sparing the rest of the immune system. The exposure of autoreactive lymphocytes to increased doses of self-antigens may result in deletion or anergy which, in turn, can lead to prevention or suppression of the disease. Whereas this scenario may occur in certain circumstances, there are at least two factors that need to be considered: first, autoimmune diseases are likely to be associated with impaired peripheral regulatory mechanisms and secondly, once the disease becomes manifest, it may be associated with reactivity against multiple other self-antigens.
In view of these limitations, a more attractive strategy would be the generation of autoreactive cells with the ability to recognize organ specific antigens and to produce mediators that suppress the activity of pathogenic cells instead of having the potential to promote disease. For example, it would be desirable to selectively stimulate the production of immunomodulator compounds such as, for example, cytokines like IL-4, IL-10, IL-9, IL-13 and TGF-beta. It will be appreciated that the induction of such immunomodulator compounds may be associated with the identity of the selected epitope in the context of the T cell repertoire, the cytokine context during priming and the inoculation regimen/antigen timing and duration of inoculations. Significantly, it will be appreciated that such a strategy is not limited to antigens that are central to the pathogenesis of an autoimmune disease, but potentially employs any organ-specific antigen. As such, selective induction of such immunomodulator compounds has several advantages in the amelioration of autoimmune disorders. For example, such a treatment does not require identification of the those epitopes that trigger the pathogenesis rather it may offer broad-based bystander suppression of autoreactive harmful T cells against various epitopes. Moreover such a strategy would limit the risk of exacerbating the disease due to transient activation phase of pathogenic T cells during antigen therapy and it may circumvent the refractoriness of pathogenic T cells to peripheral tolerance mechanisms mediating anergy and deletion. Unfortunately, no method presently exists for selectively inducing immunomodulator compounds to reduce or prevent the symptoms associated with autoimmune disorders.